Vasopressin is a naturally occurring peptide hormone released by the posterior pituitary gland in response to conditions of rising plasma tonicity or falling blood pressure. Vasopressin is a nonapeptide possessing at least two distinctly different kinds of pharmacological properties: the vasopressor (V.sub.1) effect causing increases in blood pressure; and the antidiuretic (V.sub.2) effect which brings about reabsorption of free water in the renal tubule. Any pathological lesion that reduces the secretion of vasopressin to levels that are less than approximately 7% of normal will produce clinically apparent diabetes insipidus. Trauma, surgery in the region of the pituitary and hypothalamus, malignancy, and infiltration lesions are well-recognized causes of this condition; there are also familial and idiopathic varieties of the disease. Regardless of specific cause, the pathophysiology remains the same: polyurea and the excretion of a dilute urine.
The present therapy of choice for treating pituitary diabetes insipidus is the administration of either a naturally occurring vasopressin or a vasopressin analogue which is synthetically produced. Naturally occurring vasopressin and synthetically prepared vasopressin analogues are also effective in some cases of esophagal variceal bleeding and of colonic diverticular bleeding. Current medical practice utilizes both naturally occurring vasopressins and a variety of different synthetically produced vasopressin analogues as selective therapeutic agents based upon research investigations conducted over the last forty years. In order to better understand the goals, purposes, advantages, and achievements of the present invention, it is useful to briefly summarize the present state of knowledge concerning the chemistry and the pharmacodynamics of vasopressin and its various synthetic analogues in living subjects, particularly humans.
Naturally occurring vasopressin was structurally analyzed and completely synthesized in the laboratory by du Vigneaud and co-workers by 1954 [J. Am. Chem. Soc. 75:4879-4880 (1953); J. Am. Chem. Soc. 76:4751-4752 (1954)]. In all mammals except those in the order suina, the naturally occurring structure is [8-arginine]-vasopressin (hereinafter "AVP") having the formula of: ##STR1##
The naturally occurring peptide in the order suina was found to be [8-Lysine] vasopressin and has come to be termed "Lypressin." All naturally occurring vasopressins are nonapeptides with two cysteine residues forming a bridge between positions 1 and 6 respectively. Integrity of the disulfide bond is usually thought to be essential for retention of biological activity [The Pharmacological Basis Of Therapeutics, 7th edition (Goodman et al., editors), MacMillan Publishing Company, New York, 1985, pages 908-919]. However, it was recently reported that an intact S-S ring is not necessary for binding of antagonistic AVP analogues [Manning et al., Nature 329:839-840 (1987)].
The natural vasopressins such as AVP are subject to rapid enzymatic degradation in-vivo. Four sites of cleavage have been identified, the most important of which appear to be at positions 7-8 and 8-9 in the peptide; the disulfide bond and positions 1-2 are also sites of attack by a variety of different enzymes in the kidney, brain, liver, and uterus. The half-life of circulating vasopressin is approximately 20 minutes, with renal and hepatic catabolism occurring via reduction of the disulfide bond and peptide cleavage. A small amount of vasopressin is normally excreted, as in the urine, but urinary clearance is less than 5% of that occurring elsewhere in the body.
Naturally occurring vasopressins such as AVP interact primarily with two distinct receptor types in the organs and tissues of the body designated as V.sub.1 and V.sub.2 respectively [Michel et al., Biochem. Soc. Trans. 7:861-865 (1979)]. V.sub.1 receptors have been identified on vascular smooth muscle and in liver cells [Schiffrin and Genest, Endocrinology 113:409-411 (1983); Cantau et al., J. Recept. Res. 1:137-168 (1980)]. The stimulation of V.sub.1 receptors caues constriction of blood vessels and an increase of blood pressure. Alternatively, V.sub.2 receptors are located in the renal tubule [Guillon et al., Eur. J. Pharmacol. 85:291-304 (1982)]. The stimulation of V.sub.2 receptors in the kidney brings about reabsorption of free water in the renal tubule--the so called antidiuretic effect mediated by the formation of cyclic AMP. Much research effort has been devoted to investigating the mechanisms of receptor activation [Jard, S., Progress In Brain Research 60:383-394 (1983) and the references cited therein].
Another very active area of investigation has been the design and synthesis of specific vasopressin analogues which function as selective agonists or antagonists for each receptor type. This latter area of investigation has become the primary focus of investigators for designing and synthesizing pharmacologically active preparations [Manning and Sawyer, "Development Of Selective Agonists And Antagonists Of Vasopressin And Oxytocin," in Vasopressin (Robert W. Schrier, editor), Raven Press, New York, 1985, pages 131-144 and the references cited therein].
It is useful to recognize and note the basic distinction between synthetically prepared vasopressin agonists and to distinguish them from synthetically prepared vasopressin antagonists. By definition, vasopressin agonists are able to selectively act upon and activate a given receptor type, either V.sub.1 or V.sub.2, in order to mimic only the antidiuretic effect or the pressor effect alone. Perhaps the best known example of a V.sub.2 agonist is the widely used analogue, [1-deamino,8-D-arginine] vasopressin, termed "dDAVP" in research investigations and "desmopressin" as the trade name drug [Zaoral et al., Coll. Czech. Chem. Commun. 32:1250-1257 (1967)]. Contradistinctively, a vasopressin antagonist by definition is a vasopressin analogue which will selectively bind to but not activate a given receptor type (either V.sub.1 or V.sub.2); and which will therefore block agonistic responses at the selective receptor site [Lowbridge et al., J. Med. Chem. 21:313-315 (1978); Manning et al., J. Med. Chem. 20:1228-1230 (1977)]. Although structural parallels between agonists and antagonists of vasopressin can be drawn, it is critical to always differentiate and distinguish between the two in terms of functional and pharmacological effects.
Considerable interest and investigations have been directed to developing vasopressin analogues which are selective for either V.sub.1 or V.sub.2 receptors; and which are also either agonists or antagonists of only a single type of receptor (V.sub.1 or V.sub.2 but not both) [see Manning, M. and W. H. Sawyer, "Development Of Selective Agonists And Antagonists Of Vasopressin And Oxytocin," in Vasopressin (R. W. Schrier, editor), Raven Press, New York, 1985, pp 131-144; U.S. Pat. Nos. 4,543,349 and 4,658,015; and Lammek et al., J. Med. Chem. 31:603-606 (1988)]. Based on these developments, the critical structural requirements for substantial antidiuretic antagonism of cyclic analogues of AVP appear to involve a combination of the following modifications: a 1-mercaptocyclohexaneacetic acid residue at position 1; either D-Tyr(Et), D-Phe, D-Leu, or D-Ile at position 2; and an amino acid residue such as Val, Ala, Abu (.alpha.-amino-butyric acid), etc. at position 4. One of the presently known potent antagonists of the antidiuretic and pressor responses to AVP [Manning and Sawyer, supra] has the following structure: ##STR2##
This Manning formulation, however, represents the current limits of our knowledged and developments in this art. This general structure, together with minor substitutions at position 1 and appropriate modifications of positions 2 and 4 respectively result in anti-antidiuretic analogues of AVP. Accordingly, there remains a clear and present need for highly potent compositions having anti-vasopressor (V.sub.1) and anti-antidiuretic (V.sub.2) antagonistic properties which are demonstratably pharmacologically active after administration in-vivo. The generation of such novel potent compositions would be recognized generally as a major advance and improvement over the currently available choices by practitioners ordinarily skilled in this art.